A Novel Therapeutic Concept for Familial LCAT Deficiency: Long-Term Enzyme Replacement Using Genetically Modified Adipocytes

Masayuki KurodaJapan Speaker A Novel Therapeutic Concept for Familial LCAT Deficiency: Long-Term Enzyme Replacement Using Genetically Modified AdipocytesFamilial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder marked by defective HDL maturation, leading to corneal opacity, hemolytic anemia, and progressive renal dysfunction. No disease-modifying treatment has been established to date. Conventional enzyme replacement requires repeated administration with limited durability. Glybera, the first AAV1-based gene therapy for lipoprotein lipase deficiency, was withdrawn after limited clinical use and modest benefit. More broadly, in vivo AAV gene therapies face challenges including immune responses, hepatotoxicity at high vector doses, and considerable inter-patient variability in transgene expression. Our therapeutic approach originated from studies in diabetic mouse models, where adipocytes were explored as platforms for sustained protein delivery. These cells demonstrated endocrine-like properties and long-term protein secretion in vivo. Adipocytes are particularly suited for this purpose due to their longevity, secretory capacity, and low tumorigenic risk. Building on these findings, we established an ex vivo gene and cell therapy platform using genetically modified adipocytes (GMAC), autologous adipocyte-derived cells engineered to express therapeutic proteins. As its first application, we targeted familial LCAT deficiency. These cells were expected to engraft upon subcutaneous implantation, re-differentiate into functional adipocytes, and provide long-lasting and therapeutically relevant LCAT secretion. In a first-in-human clinical trial conducted under Japan’s regulatory framework for regenerative medicine, mature adipocytes were collected from the patient’s subcutaneous fat, converted into proliferative cells via ceiling culture, and transduced to express therapeutic human LCAT, then administered subcutaneously to the patient. Single administration of LCAT-GMAC was well tolerated with no serious adverse events. Sustained increases in serum LCAT activity were observed, accompanied by improvements in lipoprotein profiles and hemolytic anemia. A marked reduction in proteinuria was noted, and renal function remained stable throughout the follow-up period. Remarkably, serum LCAT activity persisted for over eight years after the single administration, the longest durability ever reported for enzyme replacement. This provides the first clinical evidence that ceiling culture-derived, ex vivo modified adipocytes can achieve lasting correction of systemic enzyme deficiencies. LCAT-GMAC therapy thus offers a potentially curative strategy for familial LCAT deficiency and a new paradigm for treating dyslipidemias and other lifelong plasma protein deficiencies.